supplementary_data-final.pdf (494.24 kB)

YAP Activation in Renal Proximal Tubule Cells Drives Diabetic Renal Interstitial Fibrogenesis

Download (494.24 kB)
figure
posted on 25.08.2020 by Ada Admin, Jianchun Chen, Xiaoyong Wang, Qian He, Nada Bulus, Agnes B. Fogo, Ming-Zhi Zhang, Raymond C. Harris
Increasing studies have suggested that the renal proximal tubule is a site of injury in diabetic nephropathy (DN), and progressive renal tubulointerstitial fibrosis is an important mediator of progressive kidney dysfunction in DN. In this study, we observed increased expression and activation of YAP (Yes-associated protein) in renal proximal tubule epithelial cells (RPTC) in diabetic patient and mouse kidneys. Inducible deletion of Yap specifically in RPTC or administration of the YAP inhibitor verteporfin significantly attenuated diabetic tubulointerstitial fibrosis. EGFR-dependent activation of RhoA/Rock and PI3K-Akt signals and their reciprocal interaction were upstream of proximal tubule YAP activation in diabetic kidneys. Production and release of CTGF in culture medium were significantly augmented in HEK293 transfected with a constitutively active YAP mutant, and the conditioned medium collected from these cells activated and transduced fibroblasts into myofibroblasts. This study demonstrates that proximal tubule YAP dependent paracrine mechanisms play an important role in diabetic interstitial fibrogenesis; therefore, targeting Hippo signaling may be a therapeutic strategy to prevent the development and progression of diabetic interstitial fibrogenesis.

Funding

This work was supported by funds from American Diabetes Association grant #1-18-IBS-267 (to J.C); National Institutes of Health Grant DK51265, DK62794 and DK79341 (to R.C.H and M-Z.Z.), Department of Veterans Affairs grant 00507969 (to R.C.H), and support by the Vanderbilt O’Brien Kidney Center (DK114809).

History

Exports